Toll-like receptors (TLRs) are a family of membrane-spanning receptors that are expressed on cells of the immune system like dendritic cells, macrophages, monocytes, T cells, B cells, NK cells and mast cells but also on endothelial and epithelial cells (Kawai et al., Immunity, 2011, 34, 637-650, Kawai et al., Nat. Immunol., 2010, 11, 373-384). TLRs that recognize bacterial and fungal components are expressed on the cell surface (i.e. TLR1, 2, 4, 5 and 6), while others that recognize viral or microbial nucleic acids like TLR3, 7, 8 and 9 are localized to the endolysosomal/phagosomal membrane (Henessy et al. Nat. Rev. Drug Discovery 2010, 9, 293-307). TLR activation leads to the induction and release of pro-inflammatory cytokines, with the specific activation sequence and response depending on the specific TLR and cell type. TLR7 and TLR8 are both expressed in monocytes and macrophages, with TLR7 also highly expressed in plasmacytoid dendritic cells and TLR8 in myeloid dendritic cells and mast cells. Both receptors are activated by ssRNA and their activation stimulates the production of cytokines such as IL-6, IL-12, TNF-α and IFN-γ and additional co-stimulatory molecules and chemokine receptors. Dependent on the cell type, type I interferons, IFNα (from plasmacytoid dendritic cells) and IFNβ, are also produced by cells upon activation with TLR7/8 agonists (Uematsu et al., J. Biol. Chem., 2007, 282, 15319-15323).
Small molecule agonists for both the TLR7 and TLR8 receptor as well as analogs modified for use as vaccine adjuvants or conjugates have been identified in many patents (i.e. WO1992015582, US 2003187016, WO 2005076783, WO2007024612, WO2009111337, WO2010093436, WO2011017611, WO2011068233, WO2011139348, WO2012066336, WO2012167081, WO2013033345, WO 2013067597, WO2013166110, and US2013202629). Clinical experience has been obtained using exclusively TLR7 agonists. A number of the early compounds have demonstrated anti-viral and anti-cancer properties. For example, the TLR7 agonist imiquimod (ALDARA™) was approved by the U.S. Food and Drug Administration as a topical agent for the treatment of genital warts, superficial basal cell carcinoma and actinic keratosis. Systemic application however of the early TLR7 agonists like resiquimod has been abandoned due to intolerable cardiotoxicity observed upon global chemokine stimulation at therapeutic levels (Holldack, Drug Discovery Today, 2013, 1-4). Knowledge about TLR8 agonists is less advanced and mostly restricted to data with early mixed TLR7/8 agonists like resiquimod and more recently to compounds described by VentiRX Pharmaceuticals (i.e. WO2010054215, WO2012045090). At present there is still a need for additional small molecule TLR7 and TLR8 agonists, specifically those with improved potency.
The present invention is directed to 1H-imidazo[4,5-c]quinolin-4-amine-2-methylpropan-2-yloxy derivatives with improved cellular potency over known TLR7 and/or TLR8 agonists of this type for use in the treatment of cancer, preferably solid tumors and lymphomas, and for other uses including the treatment of certain skin conditions or diseases, such as atopic dermatitis, the treatment of infectious diseases, preferably viral diseases, and for use as adjuvants in vaccines formulated for use in cancer therapy or by desensitizing of the receptors by continuous stimulation in the treatment of autoimmune diseases.
Specifically, the present invention discloses 1H-imidazo[4,5-c]quinolin-4-amine-2-methylpropan-2-yloxy derivatives that are derivatized directly on the tertiary alcohol with an aminoethyl or glycine moiety. Due to the poor reactivity of the tertiary alcohol these derivatives had obviously eluded earlier attempts at synthesis. Surprisingly, these new compounds possess high cellular potency at TLR7 that is comparable or even better than resiquimod itself, whereas close analogs that have been described earlier such as 1-(2-(2-Aminoethoxy)ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (Example 69 of US20030187016) do not show the required activity. In addition and also surprisingly, the described 1H-imidazo[4,5-c]quinolin-4-amine-2-methylpropan-2-yloxy derivatives are strong TLR8 receptor agonists with potency comparable or superior to so far disclosed TLR8 agonists from other chemical classes and much improved over resiquimod itself. Thus, the compounds of the present invention fulfil the need of activating both TLR7 and TLR8 receptors with improved potency.